P1065: CONGENITAL ERYTHROCYTOSIS DUE TO HETEROZYGOUS VARIANTS IN THE BISPHOSPHOGLYCERATE MUTASE GENE
Authors: M. J. van Dijk, B. A. van Oirschot, M. C. Stam-Slob, B. van der Zwaag, E. J. van Beers, J. J. Jans, P. van der Linden, J. M. Torregrosa Diaz, B. Gardie, F. Girodon, R. Schots, N. Thielen, R. van Wijk
Journal: HemaSphere (2022)

Background: Congenital erythrocytosis is an inherited condition characterized by increased red blood cell mass, reflected by persistently elevated hemoglobin (Hb) and hematocrit levels. Erythrocytosis can be primary due to an intrinsic defect of erythropoiesis, or secondary, including germline variants in genes involved in the oxygen-sensing pathway and Hb variants with altered oxygen affinity. A very rare cause involves variants in bisphosphoglyerate mutase (BPGM), which regulates the red blood cell concentration of 2,3-bisphosphoglycerate (2,3-BPG), an important modifier of Hb-oxygen affinity. Aims: We report three European families with erythrocytosis and partial BPGM deficiency due to heterozygosity for variants in the BPGM gene, including one novel variant. Methods: The study was performed on adults of three families with JAK2-negative erythrocytosis. DNA analysis concerned sequencing of relevant coding exons, including flanking splice-site consensus sequences, of the eight major genes involved in secondary congenital erythrocytosis (EPOR, HBB, HBA1, HBA2, VHL, EPAS1, ELGN1, and BPGM). Identified variants were evaluated using Ensembl, gnomAD, PolyPhen-2, and SIFT. BPGM enzyme activity was determined as described by Beutler. Quantitative analysis of 2,3-BPG was performed using liquid chromatography tandem mass spectrometry. Hb-oxygen affinity, reflected by p50 levels (the oxygen pressure when Hb is 50% saturated with oxygen), was analyzed using the Hemox Analyzer (TCS Scientific). Results: In the first family (Table 1), a novel missense variant (c.535C>T p.(Arg179Cys) was identified in BPGM. Both the 65-year-old mother with complaints of headaches, and her 39-year-old son with a medical history of retinal vein occlusion were heterozygous for this variant. Allele frequency in gnomAD was 3.98-5. The predicted effect ranged from either deleterious (SIFT) to benign (HumVar model of Polyphen-2). Subsequent functional analysis showed low-normal BPGM activity, whereas 2,3-BPG and p50 levels were decreased (Table 1). In the second and third families, three male individuals were heterozygous for the c.269G>A p.(Arg90His) missense variant in BPGM. This variant was only once previously reported, and has an allele frequency of 1.06-5. All affected subjects had mild erythrocytosis without any additional clinical features, and showed decreased BPGM activity, decreased 2,3-BPG levels and decreased p50 (Table 1). Image:Summary/Conclusion: We describe five individuals from three families in which heterozygosity for missense variants in BPGM is associated with congenital erythrocytosis. Our findings further strengthen the hypothesis of an autosomal dominant inheritance pattern of BPGM variants. Our data also demonstrate the added value of functional analyses to validate gene panel and in silico analysis results for their clinical relevance. Future cases may help to interpret the impact of BPGM variants on hematological and clinical phenotype.